Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration

Manganese Superoxide Dismutase (MnSOD) is an essential mitochondrial antioxidant enzyme that protects organisms against oxidative damage, dismutating superoxide radical (O2-) into H2O2 and O2. The active site of the protein presents a Mn ion in a distorted trigonal-bipyramidal environment, coordinat...

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Autores principales:	Martí, Marcelo Adrián, De Biase, Pablo Martín, Estrin, Dario Ariel, Boechi, Leonardo
Publicado:	2011
Materias:	Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00039861_v507_n2_p304_Moreno http://hdl.handle.net/20.500.12110/paper_00039861_v507_n2_p304_Moreno
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_00039861_v507_n2_p304_Moreno
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spelling	paper:paper_00039861_v507_n2_p304_Moreno2023-06-08T14:25:05Z Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration Martí, Marcelo Adrián De Biase, Pablo Martín Estrin, Dario Ariel Boechi, Leonardo Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine Manganese Superoxide Dismutase (MnSOD) is an essential mitochondrial antioxidant enzyme that protects organisms against oxidative damage, dismutating superoxide radical (O2-) into H2O2 and O2. The active site of the protein presents a Mn ion in a distorted trigonal-bipyramidal environment, coordinated by H26, H74, H163, D159 and one -OH ion or H2O molecule. The catalytic cycle of the enzyme is a "ping-pong" mechanism involving Mn3+/Mn2+. It is known that nitration of Y34 is responsible for enzyme inactivation, and that this protein oxidative modification is found in tissues undergoing inflammatory and degenerative processes. However, the molecular basis about MnSOD tyrosine nitration affects the protein catalytic function is mostly unknown. In this work we strongly suggest, using computer simulation tools, that Y34 nitration affects protein function by restricting ligand access to the active site. In particular, deprotonation of 3-nitrotyrosine increases drastically the energetic barrier for ligand entry due to the absence of the proton. Our results for the WT and selected mutant proteins confirm that the phenolic moiety of Y34 plays a key role in assisting superoxide migration. © 2010 Elsevier Inc. All rights reserved. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:De Biase, P.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Boechi, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2011 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00039861_v507_n2_p304_Moreno http://hdl.handle.net/20.500.12110/paper_00039861_v507_n2_p304_Moreno
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine
spellingShingle	Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine Martí, Marcelo Adrián De Biase, Pablo Martín Estrin, Dario Ariel Boechi, Leonardo Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
topic_facet	Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine
description	Manganese Superoxide Dismutase (MnSOD) is an essential mitochondrial antioxidant enzyme that protects organisms against oxidative damage, dismutating superoxide radical (O2-) into H2O2 and O2. The active site of the protein presents a Mn ion in a distorted trigonal-bipyramidal environment, coordinated by H26, H74, H163, D159 and one -OH ion or H2O molecule. The catalytic cycle of the enzyme is a "ping-pong" mechanism involving Mn3+/Mn2+. It is known that nitration of Y34 is responsible for enzyme inactivation, and that this protein oxidative modification is found in tissues undergoing inflammatory and degenerative processes. However, the molecular basis about MnSOD tyrosine nitration affects the protein catalytic function is mostly unknown. In this work we strongly suggest, using computer simulation tools, that Y34 nitration affects protein function by restricting ligand access to the active site. In particular, deprotonation of 3-nitrotyrosine increases drastically the energetic barrier for ligand entry due to the absence of the proton. Our results for the WT and selected mutant proteins confirm that the phenolic moiety of Y34 plays a key role in assisting superoxide migration. © 2010 Elsevier Inc. All rights reserved.
author	Martí, Marcelo Adrián De Biase, Pablo Martín Estrin, Dario Ariel Boechi, Leonardo
author_facet	Martí, Marcelo Adrián De Biase, Pablo Martín Estrin, Dario Ariel Boechi, Leonardo
author_sort	Martí, Marcelo Adrián
title	Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
title_short	Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
title_full	Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
title_fullStr	Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
title_full_unstemmed	Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
title_sort	exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
publishDate	2011
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00039861_v507_n2_p304_Moreno http://hdl.handle.net/20.500.12110/paper_00039861_v507_n2_p304_Moreno
work_keys_str_mv	AT martimarceloadrian exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT debiasepablomartin exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT estrindarioariel exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT boechileonardo exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration
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Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration

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